title: Metronomic S-1 chemotherapy and vandetanib: an efficacious and nontoxic treatment for hepatocellular carcinoma.
abstract: BACKGROUND
  Metronomic chemotherapy involves frequent, regular administration of cytotoxic drugs at nontoxic doses, usually without prolonged breaks. We investigated the therapeutic efficacies of metronomic S-1, an oral 5-fluorouracil prodrug, and vandetanib, an epidermal growth factor receptor and vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, in models of hepatocellular carcinoma (HCC).
  
  
  METHODS
  We compared anti-HCC effects and toxicity in the six treatment groups: control (untreated), maximum tolerated dose (MTD) S-1, metronomic S-1, vandetanib, MTD S-1 with vandetanib, and metronomic S-1 with vandetanib. Tumor microvessel density (MVD) and tumor apoptosis were evaluated by immunohistochemistry. The expression of VEGF and thrombospondin-1, an endogenous inhibitor of angiogenesis, was analyzed by Western blot.
  
  
  RESULTS
  Metronomic S-1 significantly inhibited tumor growth, which was enhanced by combination with vandetanib. With respect to toxicities, MTD S-1 caused severe body weight loss and myelosuppression, whereas metronomic S-1 did not cause any overt toxicities. Moreover, metronomic S-1 or metronomic S-1 with vandetanib prolonged survival, the latter treatment providing the greatest benefit. Metronomic S-1 and metronomic S-1 with vandetanib decreased MVDs and increased apoptosis in tumor tissues. The expression of VEGF in tumor tissues was upregulated by vandetanib and metronomic S-1 with vandetanib, whereas the expression of thrombospondin-1 was upregulated by metronomic S-1 and metronomic S-1 with vandetanib.
  
  
  CONCLUSIONS
  Metronomic S-1 with an antiangiogenic agent seems to be an effective and safe therapeutic strategy for HCC.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan. iwamoto_hideki@med.kurume-u.ac.jp
authors.forename: Hideki
authors.initials: H
authors.lastname: Iwamoto
authors.forename: Takuji
authors.initials: T
authors.lastname: Torimura
authors.forename: Toru
authors.initials: T
authors.lastname: Nakamura
authors.forename: Osamu
authors.initials: O
authors.lastname: Hashimoto
authors.forename: Kinya
authors.initials: K
authors.lastname: Inoue
authors.forename: Junichi
authors.initials: J
authors.lastname: Kurogi
authors.forename: Takashi
authors.initials: T
authors.lastname: Niizeki
authors.forename: Reiichiro
authors.initials: R
authors.lastname: Kuwahara
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Abe
authors.forename: Hiromori
authors.initials: H
authors.lastname: Koga
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Yano
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kerbel
authors.forename: Takato
authors.initials: T
authors.lastname: Ueno
authors.forename: Michio
authors.initials: M
authors.lastname: Sata
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D049109:Cell Proliferation / Q000187:drug effects; D004338:Drug Combinations; D066246:ErbB Receptors / Q000378:metabolism; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010094:Oxonic Acid / Q000008:administration & dosage; D010880:Piperidines / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D005641:Tegafur / Q000008:administration & dosage; D014407:Tumor Cells, Cultured
chemical_list: D004338:Drug Combinations; D010880:Piperidines; D011799:Quinazolines; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D066246:ErbB Receptors; D005472:Fluorouracil; C452423:vandetanib